The objective of the proposed research is to develop methods to increase (or decrease) the rate of ethanol metabolism for the treatment of acute and chronic alcoholism. Since liver alcohol dehydrogenase catalyzes a rate-limiting step in the removal of alcohol from the blood, we propose to develop active-site-directed reagents that will increase (or decrease) the activity of the enzyme in vivo. Ethanol metabolism could be accelerated by the use of an innocuous oxidizing agent that reacts with the alcohol dehydrogenase-NADH complex to regenerate NAD ion. Compounds that could participate in this coupled reaction will be sought. Modification of one amino group per active site of the horse liver enzyme increases the activity in vitro; the human enzyme can also be activated. The role of the amino group in the mechanism of action of the enzyme will be defined by kinetic studies on modified enzyme. The location of the amino group in the active site of free enzyme and the isomeric enzyme-coenzyme complexes will be determined from chemical modification, substrate and inhibitor binding, and X-ray crystallographic studies. Based on the topography of the active site, reagents will be made that should specifically modify the amino group and activate the enzyme. Ethanol metabolism could be inhibited by compounds that inhibit or inactivate alcohol dehydrogenase. Chemical modification of methionine residues in the active site of the dehydrogenase inactivates the enzyme. Based on the structure of the active site and the location of these methionines, reagents that specifically modify the methionines will be designed. Reagents that specifically activate (or inactivate) the enzyme in vitro will be evaluated in vivo. Specific reagents that are not too toxic and meet other pharmacological criteria could be used eventually for therapy. They would also be valuable for studying the metabolism and toxicology of ethanol.